vancomyciin

7/30/2019 vancomyciin

1/31

VANCOMYCINGroup 5

R.M 2


2/31

Class: Glycopeptide

antibiotic

MOA: Inhibition of bacterialcell wall synthesis by binding

D-ala-D-ala

Goodman & Gilmans The Pharmacological Basis of Therapeutics 11th Ed. (2006)


3/31

IV, PO

Spectrum: Gram (+)

Drug of Choice MRSA

Indications IV: Serious methicillin-resistant Staphylococcal infections: pneumonia,

endocarditis, osteomyelitis, SSSI

PO: pseudomembranous colitis (metronidazole preferred)

Staphylococcal infections in Penicillin allergic patients

NOTE: Do not use in non-Penicillin allergic patients. Vancomycin does not

kill as rapidly as antistaphylococcal -lactams, and may negatively impactclinical outcome

Unique Qualities Monitor trough serum concentrations

Poor oral absorption

Adjust dose for renal impairment

ADRs RedMan Syndrome

Ototoxicity

Nephrotoxicity w/ other nephrotoxic agents


4/31

introduction

Vancomycin is a glycopeptide antibiotic used to

treat severe gram-positive infections due to

organisms that are resistant to other antibiotics

such as methicillin-resistant staphylococci andampicillin-resistant enterococci.

It is also used to treat infections caused by othersensitive gram-positive organisms in patients that

are allergic to penicillins.


5/31

Penicillin binding

protein

Peptidoglycan Synthesis


6/31

Vancomycin is bactericidal and exhibits time-

dependent or concentration-independentbacterial killing.

Antibiotics with time-dependent killingcharacteristically kill bacteria most effectively

when drug concentrations are a multiple

(usually three to five times) of the minimuminhibitory concentration (MIC) for the bacteria


7/31

The mechanism of action

The mechanism of action for vancomycin isinhibition of cell wall synthesis in susceptiblebacteria by binding to the D-alanyl-D-alanine

terminal end of cell wall precursor units

Inhibition of cell wall synthesis: target is mureinmonomers peptidoglycan precursors.

Glycopeptides bind to the terminus region of thepentapeptide forms a stable complex cantbe incorporated into the growing cell wall


8/31

Enterococcus: Van A E Peptidoglycan precursor has decreased affinity

for vancomycin D-ala-D-ala replaced by D-ala-D-lac

Staphylococcus aureus (MIC < 2 mcg/mL; Inhib 48 mcg/mL, > 16 Resist):

VISA isolates:

Increased amount of precursor withdecreased affinity

Thicker cell wall

hVISA: heterogenous bacterial population

Mechanism of resistance:


9/31

THERAPEUTIC AND TOXIC

CONCENTRATIONS

Vancomycin is administered as a short-term

(1-hour) intravenous infusion.

Infusion rate related side effects have been

noted when shorter infusion times (~30

minutes or less) have been used.


10/31


11/31

the therapeutic range for steady-state peak

concentrations is usually considered to be

2040 g/mL

ototoxicity has been reported when

vancomycin serum concentrations exceed

80 g/mL


12/31

We should monitor for signs and symptoms

that may indicate ototoxicity is occurring in apatient.

auditory: tinnitus, feeling of fullness or

pressure in the ears, loss of hearing

acuity in the conversational range;

vestibular: loss of equilibrium, headache,

nausea, vomiting, vertigo, dizziness,

nystagmus, ataxia).


13/31

the average vancomycin MICs for Staphylococcusaureus and Staphylococcus epidermidis are 12

g/mL

minimum predose or trough steady-stateconcentrations equal to 510 g/mL are usuallyadequate to resolve infections with susceptibleorganisms.

Methicillin-resistant S. aureus (MRSA) with MICsof 1.52 g/mL mayrequire higher steady-statetrough concentrations to achieve a clinical cure


14/31

Vancomycin penetrates into lung tissue poorly

(average serum:tissue ratio of 6:1) andpulmonary concentrations are highly variable

among patients

Based on these findings and reports of

therapeutic failures, recent treatment

guidelines for hospital-aquired pneumoniarecommend vancomycin steady-state trough

concentrations equal to 1520 g/mL


15/31

vancomycin steady-state concentrations

above 15 g/mL are related to an increased

incidence ofnephrotoxicity.


16/31

Nephrotoxicity and ototoxicity cannot be

completely avoided when using vancomycinby keeping serum concentrations within the

suggested ranges.

However, by adjusting vancomycin dosage

regimens so that potentially toxic serum

concentrations are avoided, drugconcentration-related adverse effects should

be held to the absolute minimum.


17/31

CLINICAL MONITORING PARAMETERS

to monitor both steady-state peak and

trough vancomycin serum concentrations

serum creatinine concentrations

Ideally, a baseline serum creatinine

concentration is obtained before

vancomycin therapy is initiated and three

times weekly during treatment.

clinical signs and symptoms of auditory


18/31


19/31

Oral bioavailability is poor (


20/31


21/31

Normal Patients

The recommended dose for vancomycin in

patients with normal renal function is 30

mg/kg/d given as 2 or 4 divided daily doses.

In normal weight adults, the dose is usually 2

g/d given as 1000 mg every 12 hours.


22/31

EFFECTS OF DISEASE STATES AND CONDITIONS ON

VANCOMYCIN PHARMACOKINETICS AND DOSING

Nonobese adults with normal renal function

(creatinine clearance >80 mL/min) have an

average vancomycin half-life of 8 hours (range

= 79 hours)

the average volume of distribution for

vancomycin is 0.7 L/kg (range 0.51.0 L/kg) in

this population.


23/31

Burn Patients Major body burns (>3040% body surface area) can

cause large changes in vancomycinpharmacokinetics.

48 to 72 hours after a major burn, the basal

metabolic rate of the patient increases to facilitatetissue repair. The increase in basal metabolic ratecauses an increase in glomerular filtration ratewhich increases vancomycin clearance.

Because of the increase in drug clearance, theaverage half-life for vancomycin in burn patients is4 hours.


24/31

Obesity

Obese individuals with normal serum creatinineconcentrations have increased vancomycin clearancesecondary to increased glomerular filtration rate and arebest dosed with vancomycin using total body weight.

The reason for the increased drug clearance is kidneyhypertrophy which results in larger creatinine clearancerates.

Volume of distribution does not significantly change withobesity and is best estimated using ideal body weight (IBW)in patients more than 30% overweight (>30% over IBW, V=0.7 L/kg IBW)


25/31

Because the primary pharmacokinetic change forvancomycin in obesity is increased drug clearancewith a negligible change in volume of distribution

average half-life decreases to 3.3 hours

While the average dose in morbidly obese and normalweight patients with normal serum creatinineconcentrations was ~30 mg/kg/d using total body

weight in both populations, some morbidly obese patients required every-8-hour

dosing to maintain vancomycin steady-state troughconcentrations above 5 g/mL.30


26/31

Premature infants Premature infants (gestational age 32 weeks) have a larger

amount of body water compared to adults.

However, vancomycin volume of distribution (V = 0.7 L/kg)is not greatly affected by these greater amounts of bodywater as is the case with aminoglycoside antibiotics.

Kidneys are not completely developed at this early age soglomerular filtration and vancomycin clearance (15mL/min) are decreased.

A lower clearance rate with about the same volume ofdistribution as adults results in a longer average half-life forvancomycin in premature babies (10 hours)


27/31

Persamaan Parameter Farmakokinetik

Vancomisin

CLvanco (mL/min/kg) = (0.695 x CLcr [mL/min/kg] + 0.05


28/31

Pharmacokinetic Parameters ComparisonAmong Models

1. Estimate CLvanco based on the CLcr

2. Estimate Vd

3. Estimate Ke based4. Estimate the trough level based on

The dose given to patients

Above Ke Bolus model


29/31

Methods ComparisonMethods Equation

Kinetidex (Ke = 0.00083 x CLcr + 0.0044)

Matzke

method

CLvanco (mL/min) = (CLcrx 0.689) + 3.66 Cockcroft-Gault

method, ABW

V=0.72L/kg if CLcris >60mL/min;

V=0.89L/kg if CLcris 10 -60 mL/min;V=0.9L/kg if CLcris


30/31

Reference

1. Birt JK, Chandler MH. Using clinical data to determine vancomycin dosingparameters. Ther Drug Monit. 1990; 12:2069.

2. Matzke GR, McGroy RW, Halstenson CE et al. Pharmacokinetics of vancomycin inpatients with various degrees of renal function. Antimicrob Agents Chemother. 1984;25:4337.

3. Burton ME, Gentle DL, Vasko MR. Evaluation of a Bayesian method for predictingvancomycin dosing. DICP. 1989; 23:294300.

4. Rodvold KA, Blum RA, Fischer JH et al. Vancomycin pharmacokinetics in patients with

various degrees of renal function. Antimicrob Agents Chemother. 1988; 32:84852.5. Rodvold KA, Blum RA, Fischer JH et al. Vancomycin pharmacokinetics in patients with

various degrees of renal function. Antimicrob Agents Chemother. 1988; 32:84852.

6. Ambrose PJ, Winter ME. Vancomycin. In: Winter ME. Basic clinical pharmacokinetics,4th ed. Philadelphia: Lippincott Williams & Wilkins; 2004:45176.

7. Bauer LA. Applied clinical pharmacokinetics. New York: McGraw Hill, MedicalPublishing Division; 2001:180261.

8. Murphy, J. et. Al. Predictability of Vancomycin Trough Concentrations Using SevenApproaches for Estimating Pharmacokinetic Parameter. American Journal of Health-System Pharmacy. 2006:63(23)2365-2370.


31/31

Thanks

For Your

Attention

Documents

vancomyciin